Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics.

The effect of the selective dopamine D2 receptor agonist quinpirole, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2A receptor antagonist ketanserin on catalepsy induced by atypical antipsychotics clozapine, risperidone, olanzapine and sertindole at higher doses was studied in rats. Haloperidol (0.5, 1 and 2 mg/kg), clozapine (50 and 75 mg/kg) and olanzapine (15 and 30 mg/kg) produced catalepsy dose-dependently while sertindole at doses up to 40 mg/kg failed to produce catalepsy in rats. However, sertindole (15, 30 and 45 mg/kg) produced a cataleptic effect in mice in a dose-dependent manner. At a high dose (5 mg/kg), risperidone produced catalepsy in rats. Quinpirole (0.05 and 0.1 mg/kg) reversed the cataleptic effect of haloperidol (2 mg/kg), risperidone (5 mg/kg), olanzapine (30 mg/kg) and sertindole (45 mg/kg). Quinpirole (0.05 and 0.1 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15 and 0.3 mg/kg) dose-dependently reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg) without affecting the cataleptic effect of olanzapine. However, the higher dose (0.45 mg/kg) of 8-OH-DPAT reversed it significantly. 8-OH-DPAT (0.3 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15, 0.3 and 0.45 mg/kg) failed to reverse sertindole-induced catalepsy. Ketanserin (0.75 and 1.5 mg/kg) completely reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg). Ketanserin (0.75 and 1.5 mg/kg) dose-dependently reversed olanzapine (30 mg/kg) and sertindole (45 mg/kg)-induced catalepsy without any effect on clozapine (75 mg/kg)-induced catalepsy. A higher dose (3 mg/kg) of ketanserin reversed clozapine-induced catalepsy. The present study suggests that atypical antipsychotics show fewer extrapyramidal symptoms (EPS) due to greater modulation of the serotonergic system. Therefore, an antipsychotic with dopamine D2/5-HT2A antagonistic action and 5-HT1A agonistic action may prove to be superior to the existing antipsychotics.